Pitavastatin downregulates expression of the macrophage type B scavenger receptor, CD36. Academic Article uri icon

Overview

MeSH

  • Animals
  • Cell Line
  • Cells, Cultured
  • Down-Regulation
  • Gene Expression Regulation
  • Humans
  • Mice
  • Mice, Inbred C57BL
  • Receptors, Cytoplasmic and Nuclear
  • Transcription Factors
  • Transcription, Genetic

MeSH Major

  • Hydroxymethylglutaryl-CoA Reductase Inhibitors
  • Macrophages
  • Quinolines

abstract

  • Pitavastatin (NK-104) is a novel inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, the rate-limiting enzyme for cholesterol biosynthesis. In clinical trials, pitavastatin has been shown to significantly decrease serum LDL cholesterol and triglyceride levels and increase HDL cholesterol. Scavenger receptor-mediated accumulation of oxidized LDL (OxLDL)-derived cholesteryl ester is considered to be a critical step in the development of atherosclerotic foam cell formation. We studied the effect of pitavastatin on CD36 (a class B scavenger receptor) expression by murine macrophages. Treatment of J774 cells and murine peritoneal macrophages with pitavastatin decreased CD36 mRNA expression in a dose-dependent manner. Decreased CD36 mRNA was associated with decreased CD36 cell surface protein expression in human THP-1 cells and human monocyte-derived macrophages. Pitavastatin also reduced the increase in CD36 mRNA, cell surface protein, and binding/uptake of OxLDL induced by peroxisome proliferator-activated receptor-gamma (PPARgamma) ligands and/or OxLDL. Pitavastatin did not alter the half-life of CD36 mRNA, which suggests pitavastatin downregulates CD36 expression by reducing CD36 transcription. In addition, pitavastatin significantly decreased PPARgamma mRNA and protein expression. Finally, pitavastatin increased p44/42 mitogen-activated protein kinase activity and PPARgamma phosphorylation and increased the ratio of phosphorylated PPARgamma to nonphosphorylated PPARgamma. The present data demonstrate that pitavastatin prevents OxLDL uptake by macrophages through PPARgamma-dependent inhibition of CD36 expression and suggest that pitavastatin could modulate CD36-mediated atherosclerotic foam cell formation.

publication date

  • February 17, 2004

has subject area

  • Animals
  • Cell Line
  • Cells, Cultured
  • Down-Regulation
  • Gene Expression Regulation
  • Humans
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors
  • Macrophages
  • Mice
  • Mice, Inbred C57BL
  • Quinolines
  • Receptors, Cytoplasmic and Nuclear
  • Transcription Factors
  • Transcription, Genetic

Research

keywords

  • Journal Article

Identity

Language

  • eng

Digital Object Identifier (DOI)

  • 10.1161/01.CIR.0000112576.40815.13

PubMed ID

  • 14970117

Additional Document Info

start page

  • 790

end page

  • 796

volume

  • 109

number

  • 6